title: Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies.
abstract: OBJECTIVE
  The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non-adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis.
  
  
  METHODS
  Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled.
  
  
  RESULTS
  Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1%) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers.
  
  
  CONCLUSIONS
  ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non-small-cell lung cancer, is ongoing.
authors.affiliation: Royal Marsden National Health Service Foundation Trust, The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.forename: Andre T
authors.initials: AT
authors.lastname: Brunetto
authors.forename: Nina
authors.initials: N
authors.lastname: Tunariu
authors.forename: Jorge
authors.initials: J
authors.lastname: Barriuso
authors.forename: Ruth
authors.initials: R
authors.lastname: Riisnaes
authors.forename: Lorna
authors.initials: L
authors.lastname: Pope
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clark
authors.forename: Andrew
authors.initials: A
authors.lastname: Futreal
authors.forename: Michael
authors.initials: M
authors.lastname: Germuska
authors.forename: David
authors.initials: D
authors.lastname: Collins
authors.forename: Nandita M
authors.initials: NM
authors.lastname: deSouza
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leach
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.forename: Carol
authors.initials: C
authors.lastname: Waghorne
authors.forename: Feng
authors.initials: F
authors.lastname: Chai
authors.forename: Edward
authors.initials: E
authors.lastname: Garmey
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D065731:Cytochrome P-450 CYP2C19; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004739:England; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C551661:ARQ 197; D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D017978:Receptors, Growth Factor; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human